title: Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis.
abstract: Despite high rates of exposure, only 5-10% of people infected with Mycobacterium tuberculosis will develop active tuberculosis (TB) disease, suggesting a significant role for genetic variation in the human immune response to this infection. Here, we studied TB association and expression of 18 genes involved in the Toll-like receptor (TLR) pathways. Initially, we genotyped 149 sequence polymorphisms in 375 pulmonary TB patients and 387 controls from Indonesia. We found that four polymorphisms in the TLR8 gene on chromosome X showed evidence of association with TB susceptibility in males, including a non-synonymous polymorphism rs3764880 (Met1Val; P = 0.007, odds ratio (OR) = 1.8, 95% c.i. = 1.2-2.7). We genotyped these four TLR8 polymorphisms in an independent collection of 1,837 pulmonary TB patients and 1,779 controls from Russia and again found evidence of association in males (for rs3764880 P = 0.03, OR = 1.2, 95% c.i. = 1.02-1.48). Combined evidence for association is P = 1.2x10(-3)-6x10(-4). In addition, a quantitative PCR analysis indicated that TLR8 transcript levels are significantly up-regulated in patients during the acute phase of disease (P = 9.36x10(-5)), relative to baseline levels following successful chemotherapy. A marked increase in TLR8 protein expression was also observed directly in differentiated macrophages upon infection with M. bovis bacille Calmette-Guérin (BCG). Taken together, our results provide evidence, for the first time, of a role for the TLR8 gene in susceptibility to pulmonary TB across different populations.
authors.affiliation: Infectious Diseases, Genome Institute of Singapore, Singapore, Singapore. sonia@gis.a-star.edu.sg
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
authors.forename: Ranjeeta
authors.initials: R
authors.lastname: Hari Dass
authors.forename: Hazel E E
authors.initials: HE
authors.lastname: Wong
authors.forename: Edhyana
authors.initials: E
authors.lastname: Sahiratmadja
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.forename: Bachti
authors.initials: B
authors.lastname: Alisjahbana
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Szeszko
authors.forename: Yanina
authors.initials: Y
authors.lastname: Balabanova
authors.forename: Francis
authors.initials: F
authors.lastname: Drobniewski
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Mark
authors.initials: M
authors.lastname: Seielstad
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002460:Cell Line; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007214:Indonesia; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D051200:Toll-Like Receptor 8 / Q000235:genetics* / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology*
chemical_list: D012333:RNA, Messenger; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8